External validation and updating of the infusion rate individualization of soybean oil-based intravenous lipid emulsion: A descriptive cohort study.

BACKGROUND: Safe and efficient provision of intravenous lipid emulsion (ILE) requires a strategy to individualize infusion rates. Estimating the maximum acceptable infusion rate (MaxInfRate) of soybean oil-based ILE (SO-ILE) in individuals by using a triglyceride (TG) kinetic model was reported to be feasible. In this study, we aimed to externally validate and, if needed, update the MaxInfRate estimation. METHODS: The maximum TG concentration (TGmax) in patients receiving SO-ILE at MaxInfRate was evaluated to determine if it met the definition of being <400 mg/dl for 90th percentile of patients. The TG kinetic model was evaluated through prediction performance checks and was subsequently updated using the data set of both the previous model development and present validation studies. RESULTS: Out of 83 patients, 74 had TGmax <400 mg/dl, corresponding to a probability of 89.2% (95% CI, 81.9%-95.2%), and the 90th percentile of TGmax was 400 mg/dl (95% CI, 328-490 mg/dl), closely aligned with the theoretical values. However, the individual TGmax values were biased by the infusion rate because the covariate effects were overestimated in the TG kinetic model, requiring a minor revision. The updated MaxInfRate with the combined data set showed unbiased and more accurate predictions. CONCLUSION: The MaxInfRate was validated in external inpatients and updated with all available data. MaxInfRate estimation for individuals could be an option for the safe and efficient provision of SO-ILE.

[Iliopsoas muscle hematoma after anticoagulant therapy for pyogenic thrombophlebitis that spilled over from ascending colon diverticulitis:a case report].

A 79-year-old male patient presented to our hospital with chief complaints of fever, abdominal pain, and jaundice. Laboratory data revealed marked hepatobiliary enzyme and inflammatory marker elevations, and computed tomography revealed ascending colon diverticulitis, thrombophlebitis, portal vein thrombus, and intrahepatic cholangitis. Blood culture revealed the presence of Prevotella sp. The patient was treated with anticoagulant therapy in addition to antimicrobial therapy;however, activated partial thromboplastin time prolongation remained insufficient. Antithrombin therapy was combined with the current therapy because antithrombin levels were low, which resulted in iliopsoas muscle hematoma. The hematoma resolved conservatively after discontinuing anticoagulation, and the patient was discharged after 19 days of hospitalization with improved cholangitis and diverticulitis. The portal vein thrombus remained after discharge;however, anticoagulation therapy was not restarted due to adverse events. This case was presented because of its difficult treatment.

[Jejunal stromal tumor concomitant ectopic pancreas in a young man with sarcoidosis:a case report].

During a medical health check, a 29-year-old man was presented to our hospital with iron deficiency anemia. He had no significant medical history in his family. Despite being diagnosed with ocular sarcoidosis 5 years ago, he had no vision problems. Physical examination revealed normal vital signs and a nontender abdomen;however, his eyelid conjuvitis was pale, and he became aware of fatigue when moving vigorously. He had upper gastrointestinal endoscopy and colonoscopy, but there was no evidence of bleeding detected. A contrasted mass 30mm in size was discovered on abdominal contrast-enhanced computed tomography at the dorsal wall of the proximal jejunum. Positron emission tomography showed an accumulation image in the bilateral hilar lymph and upper jejunum. A 30-mm submucosal tumor with a central depression in the upper jejunum was discovered using a double-balloon enteroscopy. We performed biopsies from the depression margin and tattoo marking on the oral side of the tumor. Even though the biopsies specimen revealed granulation tissue, the patient was referred to surgery and underwent a partial jejunum resection because the tumor was diagnosed as the cause of anemia. The operation went smoothly, and the patient was discharged on the seventh postoperative day. Histological examination showed a proliferation of densely packed spindle cells with prominent nuclear palisading. The immunohistochemical examination revealed that c-kit and CD34 were highly expressed, whereas desmin and S-100 proteins were not. Ki-67 expression demonstrated a very low proliferative index (2%). We discovered gastrointestinal stromal tumors (GIST), as well as an ectopic pancreas. GIST is extremely rare in young people, and the coexistence of ectopic pancreas and sarcoidosis has never been reported.

Effects of Zinc Acetate on Serum Zinc Concentrations in Chronic Liver Diseases: a Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial and a Dose Adjustment Trial.

The essential trace element zinc maintains liver functions. Liver diseases can alter overall zinc concentrations, and hypozincemia is associated with various hepatic pathologies. Modulating systemic zinc through dietary supplementation is potentially useful for liver diseases. We evaluated the usefulness of zinc (NPC-02; acetate formulation) supplementation. We conducted two NPC-02 studies on zinc-deficient patients (serum zinc < 70 µg/dL). Study 1: double-blind, randomized, placebo-controlled trial on 57 subjects with chronic liver diseases comparing serum zinc in patients given NPC-02 (NPC-02 group) versus placebo (Placebo group). Study 2: dose adjustment study on 43 subjects with/without liver diseases to determine proportions maintaining serum zinc target (≥ 80 µg/dL but < 200 µg/dL). In study 1, NPC-02 subjects had higher serum zinc concentrations at week 8 than Placebo subjects (83.2 ± 20.2 and 61.3 ± 12.0, respectively; P < 0.0001), and more NPC-02 than Placebo subjects achieved the serum zinc target (15/27 vs. 1/26). In study 2, the NPC-02-induced serum zinc increase was dose-dependent in subjects both with and without liver diseases (r = 0.5143, P = 0.0022 and r = 0.5753, P = 0.0005, respectively). Interestingly, there was a marginally positive correlation between serum zinc and albumin levels in subjects with but not in those without liver diseases (r = 0.4028, P = 0.0631 and r = 0.1360, P = 0.5567, respectively). NPC-02 dose-dependently increases serum zinc in hypozincemic patients, regardless of liver disease. NPC-02 is a potentially effective therapy for liver cirrhosis, in which zinc deficiency is common. Clinical trial registry number: NCT02337569, NCT02321865.

Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis.

Antimicrobial therapy is a mainstay of the management for patients with acute cholangitis and/or cholecystitis. The Tokyo Guidelines 2018 (TG18) provides recommendations for the appropriate use of antimicrobials for community-acquired and healthcare-associated infections. The listed agents are for empirical therapy provided before the infecting isolates are identified. Antimicrobial agents are listed by class-definitions and TG18 severity grade I, II, and III subcategorized by clinical settings. In the era of emerging and increasing antimicrobial resistance, monitoring and updating local antibiograms is underscored. Prudent antimicrobial usage and early de-escalation or termination of antimicrobial therapy are now important parts of decision-making. What is new in TG18 is that the duration of antimicrobial therapy for both acute cholangitis and cholecystitis is systematically reviewed. Prophylactic antimicrobial usage for elective endoscopic retrograde cholangiopancreatography is no longer recommended and the section was deleted in TG18. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Gilbert Syndrome with Concomitant Hereditary Spherocytosis Presenting with Moderate Unconjugated Hyperbilirubinemia.

We experienced a case of a 19-year-old man with Gilbert syndrome with concomitant hereditary spherocytosis. The patient presented with moderate unconjugated hyperbilirubinemia, and inherited etiology was strongly suspected. The diagnosis of Gilbert syndrome was confirmed by the genetic analysis of the UGT1A1 gene, demonstrating UGT1A1*28 and compound heterozygote UGT1A1*6. In addition, since the laboratory findings and imaging studies revealed lysemia as well as gallstone and splenomegaly, a diagnosis of hereditary spherocytosis was made as a comorbidity. Both Gilbert syndrome and hereditary spherocytosis are hereditary diseases with a high frequency, and the hyperbilirubinemia may be exacerbated when these two diseases are concomitant.

Validation of the Japanese version of the Chronic Liver Disease Questionnaire for the assessment of health-related quality of life in patients with chronic viral hepatitis.

AIM: Patients with chronic liver diseases (CLD) suffer from a variety of subjective symptoms, and the assessment of health-related quality of life (HRQOL) is crucial. The Chronic Liver Disease Questionnaire (CLDQ) is the first liver disease-specific instrument for this purpose. In this study we aimed to develop the Japanese version of CLDQ and to assess its validity and reliability in Japanese patients with chronic viral hepatitis. METHODS: The participants included 135 Japanese patients chronically infected with hepatitis B or C virus. The Japanese version of the CLDQ was developed according to the standard "back-translation" method. In addition to the Japanese version of the CLDQ, we asked the patients to fill out two other self-report questionnaires: the Japanese versions of the 36-Item Short Form Survey (SF-36) and Hospital Anxiety and Depression Scale (HADS). Then, the internal consistency, convergent and discriminant validity of the Japanese version of CLDQ were statistically examined. RESULTS: Cronbach's alpha of the Japanese version of the CLDQ was acceptable. The mean score was lower in emotional domains of the CLDQ, compared with those in somatic domains. Pearson correlations between Japanese CLDQ and SF-36 and HADS were significant. The mean of the CLDQ scores decreased in all domains in patients with liver cirrhosis compared with those in patients with chronic hepatitis. CONCLUSION: The Japanese version of the CLDQ is a reliable and valid instrument for assessment of the HRQOL of Japanese patients with chronic viral hepatitis. The results also suggest that the HRQOL of Japanese patients is mainly impaired by emotional factors rather than somatic symptoms, and significantly worsened by progression of the disease.

Benefit of cystatin C in evaluation of renal function and prediction of survival in patients with cirrhosis.

AIM: The assessment of renal function is of vital importance in management of patients with cirrhosis. While serum creatinine (Cr) is routinely used for this purpose, Cr-based estimated glomerular filtration rate (eGFR) does not reflect true renal function because of muscle wasting and impaired liver function. By contrast, cystatin C (CysC) is unrelated to muscle volume and liver function. In this study, we examined whether CysC-based GFR estimation is beneficial in assessment of renal function in patients with cirrhosis. METHODS: First, we assessed the performance of GFR-predicting equations based on serum Cr or CysC in 14 patients with cirrhosis, by comparison with inulin clearance as a gold standard of GFR (measured GFR [mGFR]). Next, in 49 patients with cirrhosis, we examined serum Cr and CysC at baseline, and examined which GFR-predicting equations were more suitable for predicting the outcome. RESULTS: In the first experiment, mGFR was 54.3 ± 23.0 mL/min, and CysC-based GFR-estimating equations had better performances compared with Cr-based equations in terms of bias, precision and accuracy. Cr-based estimated GFR (eGFRcreat) was significantly different from mGFR (P < 0.05). In the follow-up study of 49 patients (observational period, 30.7 ± 32.0 months), multivariate analysis demonstrated that CysC-based estimated GFR (eGFRcys), along with albumin, Child-Pugh grade and presence of hepatocellular carcinoma, was independently associated with overall survival (odds ratio, 4.19; 95% confidence interval, 1.44-12.2, P = 0.009). CONCLUSION: These results suggest that eGFRcys could estimate renal function and predict outcome more accurately compared with Cr-based eGFR in cirrhotic patients.

Liver Abscess With a Markedly High Level of Carbohydrate Antigen 19-9.

Serological tumor markers are useful for detection of malignancies and evaluation of disease progression. However, some markers are rarely elevated in patients with benign diseases and without malignancies. We herein present a case of a liver abscess with a highly elevated carbohydrate antigen (CA 19-9) level in both the serum and abscess fluid. The serological level of CA 19-9 decreased with treatment. Although CA 19-9 is known to be a specific tumor marker, high serum levels of CA 19-9 can be observed in patients with pyogenic liver abscesses. CA 19-9 may also be a marker for treatment response in patients with liver abscesses.

Carcinosarcoma of the liver.

Herein we present a 73-year-old man with primary carcinosarcoma of the liver, a rare malignant tumor of the liver. The case was followed up due to HBV-related liver cirrhosis. Regular check-up by ultrasound demonstrated a hyperechoic tumor in the left lobe of the liver, and he was referred and admitted to our hospital. Dynamic CT studies revealed a mostly hypoenhancing hepatic mass with a peripheral ring enhancement. Surgical resection was performed, and the resected tumor was macroscopically a simple nodular type, 3 cm in diameter, with a dense fibrous capsule. Microscopically, undifferentiated cells were dominant in the tumor, while moderately differentiated hepatocellular carcinoma (HCC) were also observed. A transitional zone was noted between the undifferentiated tumor and HCC. Tumor tissue with adenocarcinoma, osteosarcoma and chondrosarcoma were also detected. Immunohistochemical studies demonstrated that tumor cells were HepPar 1 positive in hepatocellular carcinoma, and CK19 and partly CK7 positive in adenocarcinoma. Moreover, CD56, chromogranin A and c-kit were occasionally positive in undifferentiated tumor cells. The diagnosis of carcinosarcoma was made based on the concomitant presence of HCC and sarcomatous components, yet it is noteworthy that various types of tumor cells were observed.

Autoimmune neutropenia due to antineutrophil antibodies in a patient with primary sclerosing cholangitis.

Autoimmune neutropenia (AIN) is defined as a decrease in the circulating absolute neutrophil count (ANC) to less than 1500/µl caused by serum antineutrophil antibodies. Secondary AIN is associated with various autoimmune diseases. Herein we present the case of a patient with primary sclerosing cholangitis (PSC) who developed secondary AIN. A 19-year-old man was admitted due to liver injury, and a diagnosis of PSC was established by cholangiogram and liver biopsy. Severe neutropenia, with the ANC down to 130/µl, developed during his hospital course. No medications had been given at that time and bone marrow aspiration revealed no abnormality. Therefore we suspected secondary AIN as a causative etiology and examined whether antineutrophil antibodies were detectable in the patient's sera by flow cytometric analysis of the granulocyte indirect immunofluorescence test. We found that antineutrophil antibody was strongly positive on admission, and the titer decreased along with recovery from neutropenia. This is the first reported case of a patient with PSC who developed AIN, with detection of serum antineutrophil antibodies.

Outcome and prognostic factors of 391 Japanese patients with primary sclerosing cholangitis.

OBJECTIVES: We performed a national survey in 2003, and demonstrated characteristic features of primary sclerosing cholangitis (PSC) patients in Japan. In this study, we aimed to clarify the outcome and prognostic factors of Japanese PSC patients. METHODS: Questionnaires were sent to gastroenterologists in Japan, and 391 patients with PSC were registered and enrolled in the current study. The median follow-up was 5.3 years (range 0.1-20.8 years). The cumulative incidence for survival was analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox-proportional hazards regression model for determining prognostic variables. RESULTS: The estimated median survival of all patients was 13.1 years, with a 5-year survival rate of 74.5%. Thirty-eight patients (9.7%) who underwent liver transplantation (LT) had a 5-year survival rate of 92.0%. Both univariate and multivariate analysis demonstrated that younger age [below 49 years old; odds ratio (OR)=1.76, 1.12-2.76, P=0.0136] and lower total bilirubin (below 3.0 mg/dl; OR=2.50, 1.60-3.89, P

Analysis of 388 cases of primary sclerosing cholangitis in Japan; Presence of a subgroup without pancreatic involvement in older patients.

We analyzed 388 cases of primary sclerosing cholangitis (PSC) in Japan, according to a questionnaire sent to gastroenterologists. There was male predominance (59%), and interestingly there were two peaks in the age distribution as seen in the previous study. Jaundice and itching, major symptoms in PSC patients included in the diagnostic criteria, were observed only 28 and 16%, respectively. Alkaline phosphatase level was less than twofold of the upper limit of the normal range in 35%. In this regard, the diagnostic criteria in 2003 from Mayo Clinic, including cholestatic symptoms and two to three-fold increases in serum alkaline phosphatase, should be modified in Japan. Inflammatory bowel diseases were complicated in 37%, and autoimmune pancreatitis (AIP) in 7.2%. PSC cases with inflammatory bowel diseases were younger than the average, creating the first peak in the age distribution, and have similar characteristics compared to patients with PSC in foreign countries. By contrast, those with AIP, who were more than 50 years old, responded well to corticosteroid therapy. In addition, even after the exclusion of cases of sclerosing cholangitis complicated with AIP, the second peak in the age distribution was clearly evident. Therefore, we conclude that PSC patients without apparent involvement of the pancreas are present in the older patients and seem to be specific in Japan.

Comparison of urinary excretion of pravastatin and temocapril in bile duct-ligated rats and Eisai hyperbilirubinemic rats (EHBR).

BACKGROUND/PURPOSE: In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion. METHODS: In the present study, the urinary excretion of pravastatin and temocapril was studied in bile-duct-ligated rats (BDLR) for 3 days and in Eisai hyperbilirubinemic rats (EHBR). After urinary bladder cannulation, radiolabeled pravastatin and temocapril were injected intravenously. Urine samples were collected every 1 h for 4 h, and the radioactivity was counted. RESULTS: Urinary excretion of pravastatin was markedly increased in BDLR (85.9% of the dose after 4 h) and moderately increased in EHBR (35.9% of the dose after 4 h) compared with that in control rats (5.5% of the dose after 4 h). Similar but less prominent differences were observed with temocapril after it was administered (50.7%, 38.2%, and 22.0% of the dose after 4 h in BDLR, EHBR, and the controls, respectively). CONCLUSIONS: The absence of biliary excretion of anionic drugs was compensated for by urinary excretion in BDLR and EHBR, and the compensation was more efficient with pravastatin than with temocapril. In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion.

Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the International Consensus Meeting.

Two hundred and eighty seven Japanese cases of drug induced liver injury were assessed by the diagnostic scale of the International Consensus Meeting (ICM). They were classified to the hepatocellular (55%), mixed (24%) and cholestatic (22%) type according to the type of liver injury. Five cases were diagnosed as 'unrelated', since the reaction occurred more than 15 days after stopping the drug. The remaining 282 cases were classified to 69 cases of 'highly probable', 170 cases of 'probable', 39 cases of 'possible', and four cases of 'unlikely'. The cases with positive drug-lymphocyte stimulation test (DLST) and with eosinophilia distributed to higher scores. Although the diagnostic scale of the ICM was found to be also useful for Japanese cases, the modification of the scale including the data of DLST and eosinophilia together with some other modifications were recommended in the view of the present status of Japan. Using the modified diagnostic scale, the 287 cases were classified to 173 cases of 'highly probable', 102 cases of "probable', 11 cases of 'possible', and one case of 'unlikely'. Although the modified diagnostic scale seems better than the original one, further assessment of the modified scale using many Japanese cases is needed for the further improvement of the scale.

Abdominal ultrasonogram of autoimmune pancreatitis: Five cases of pancreatic lesions accompanied by Sjögren syndrome.

The concept of autoimmune pancreatitis has recently been established, and ultrasonographic findings we obtained from five cases consistent with autoimmune pancreatitis are reported here. Case 1, a 77-year-old man, was admitted complaining of loss of body weight. Serum hepatobiliary enzymes and γ-globulin levels were elevated, and antinuclear antibody was positive, Abdominal ultrasonography showed dilatation of the intrahepatic bile duct, wall thickening of the common bile duct and hypoechoic swelling of the pancreatic head and body. ERCP revealed multiple stenosis of the intra-and extra-hepatic bile ducts, and diffuse irregular narrowing of the main pancreatic duct. The patient complained of thirst, and the minor salivary gland was examined histologically. Our diagnosis was Sjögren syndrome accompanied by sclerosing cholangitis and a pancreatic lesion. Obstructive jaundice also developed, and PTCD was therefore performed. Both the pancreatic swelling and multiple stenosis of the bile duct improved after steroids were administered. Case 2, a 71-year-old man, was admitted with jaundice. Abdominal ultrasonography showed hypoechoic swelling of the pancreas. ERCP showed stenosis of the common bile duct in the pancreatic head region and diffuse irregular narrowing of the main pancreatic duct. Histological examination of the minor salivary gland suggested Sjögren syndrome. Steroids were therefore administered because the presence of both hyper-γ-globulinemia and positive antinuclear antibody suggested involvement of the autoimmune mechanism. Steroid therapy improved the jaundice as well as the findings from the cholangiograms and pancreatograms. We also encountered three similar cases, all consistent with the concept of autoimmune pancreatitis. The ultrasonographic findings of the pancreatic lesion (1) showed them as homogeneous and markedly hypoechoic areas and, (2) visualized the main pancreatic duct in the lesion, which facilitated a differential diagnosis of the neoplastic lesions. (3) Steroid therapy effectively decreased the hypoechoic area; in some cases, however, a hypoechoic area remained around the main pancreatic duct.